Lyme disease is a complex multisystem disorder caused by the spirochete Borrelia burgdorferi and the most common vector-borne illness in North America. Lyme arthritis is one of the major manifestations. Several features that parallel human Lyme disease are consistently induced in the murine model, including arthritis. In the model of severe combined immunodeficiency (SCID) mice, B. burgdorferi infection causes destructive arthritis. The genome of B. burgdorferi consists of a chromosome and up to 21 linear and circular plasmids. In vitro propagation of B. burgdorferi is associated with plasmid loss and loss of plasmids is coupled with decreased infectivity and pathogenicity. We have generated a spirochete variant that is fully infectious in SCID mice but unable to induce arthritis in this model. Plasmid content analysis revealed that four plasmids that were present in arthritis-virulent strains had been missing from the nonpathogenic variant, suggesting that these plasmids may carry arthritis-virulent genes. We will first determine which of the plasmids are essential for the induction of arthritis. To achieve this goal, variants with different plasmid contents will be generated and examined for infectivity and arthritis virulence. Once arthritis-related plasmids are identified, we will be able to focus on arthritis-virulent genes. Unique genes encoded on the arthritis-virulent plasmids will be selectively inactivated and then complemented to examine the influence of these genes on the induction of arthritis.